经门静脉途径灌注化疗时5-Fu在肝脏和血液中的浓度和药动学特点

目的研究经门静脉途径灌注化疗时5-Fu在肝脏和血液中的浓度和药动学特点,并与外周静脉注射化疗相比较,探讨区域性门静脉灌注化疗的优势。方法 24只Wistar大鼠随机分组后分别经门静脉插管区域灌注及经外周静脉注射5-Fu,剂量均为20 mg/kg。采用高效液相色谱法(HPLC)测定两组给药后5、10、20、30、45、60、90、120、180 min不同时间点血浆和肝脏组织中5-Fu的浓度,对比两组5-Fu在肝脏和血浆中的药动学数据。对比两组的穿透比率、穿透指数及治疗优势度。结果经外周静脉注射5-Fu时,肝脏组织中的药物峰浓度(Cmax)和药物时量曲线下面积(AUC)分别为(13.79±4.56)μg/g及(342.20±108.20)μg·h/ml;血浆中的Cmax和AUC分别为(36.85±5.96)μg/g及(842.00±158.00)μg·h/ml。经门静脉灌注时,肝脏组织中的Cmax和AUC分别为(28.21±4.46)μg/g及(733.60±180.30)μg·h/ml;血浆中的Cmax和AUC分别为(21.02±4.06)μg/g及(529.80±111.50)μg·h/ml。门静脉灌注化疗与外周静脉注射相比的治疗优势度为3.37。结论与外周静脉注射全身化疗比较,区域性门静脉灌注5-Fu化疗可显著提高肝脏组织中的药物时-量作用强度,同时减少化疗药物在外周血中的分布,可作为肝癌化疗有效的给药途径     

卵巢癌腹腔化疗的药代动力学特征

目的探讨卵巢癌腹腔化疗药物的药代动力学特征.方法10例原发性卵巢上皮性癌患者,手术后1周行以DDP+5-FU为主的腹腔化疗, 剂量为DDP 60 mg/m2,5-FU 750 mg/m2.于腹腔注射完毕后0.5、1、2、6、24小时分别取血样,用HPLC及原子吸收光谱法分别测定血清5-FU和总铂浓度.数据以药代动力学软件3P87处理.结果腹腔注射后,5-FU、DDP血清平均浓度的变化过程符合一级吸收的单室药代动力学模型.其参数分别为5-FUKe = 0.45±0.18 /h、Ka = 7.59±4.63 /h、T(peak) = 0.87±0.30 h、C(max) = 2.46±1.12 μg/ml、AUC = 8.38±4.71 蘥*h/ml、Vd=316±69.4 ml/kg;DDPKe = 0.014±0.01 /h、Ka = 1.31±1.03 /h、T(peak) = 4.72±2.81 h、C(max) = 0.85±0.28 μg/ml、AUC = 85.6±55.7 μg*h/ml 、Vd = 60.3±32.6 ml/kg.5-FU,AUC0～24h = 8.4 μg*h/ml;DDP,AUC0～24h = 14.4 μg*h/ml.结论从药代动力学方面看,腹腔化疗中5-FU的AUC不低于相同剂量静脉给药,DDP的AUC低于相同剂量静脉给药.Ζ     

氟比洛芬酯注射液犬静脉给药急性毒性试验研究

目的:采用近似致死量法,考察氟比洛芬酯注射液对Beagle犬单次静脉给药可能产生的急性中毒症状和毒性靶器官,评价其安全性。方法:按照50%递增法设计剂量序列,给药顺序为96、216、324和486 mg/kg,每个剂量1只动物,单次给药,观察14d。主要观察指标包括动物一般状况、体质量、摄食量、体温、心电图分析、眼科检查、血液细胞学、血液生化学和凝血功能,对死亡或濒死动物及实验结束时处死的动物进行尸检和病理组织学检查。结果:所有动物给药时均出现轻重不等的毒性症状。给药剂量为96和216 mg/kg的动物给药后逐渐恢复正常,病检仅显示消化道黏膜充血、出血。给药剂量为324 mg/kg的动物给药后第4天突然加重,出现柏油样大便,第9天死亡。给药剂量为486 mg/kg的动物给药后极度衰弱,并出现严重上消化道出血,于第9天死亡。结论:氟比洛芬酯注射液犬单次静脉给药近似致死量范围为216～324 mg/kg,按体表面积计算约为人拟临床用等效剂量的63.2～94.8倍。该药品主要的靶器官为胃、肠、肝、胆、肾。     

肿瘤患者单次和多次口服替吉奥片的药动学研究

目的:评价肿瘤患者单次和多次口服替吉奥片的药动学特征.方法:设单次给药组10例,给药剂量60 mg;连续给药组9例,每次给药剂量60 mg,1日2次,连续服用7 d.采用液相色谱-串联质谱法测定血浆中替加氟及其代谢物5-氟脲嘧啶(5-FU)、吉美嘧啶(CDHP)和奥替拉西(Oxo)的浓度.采用DAS2.0药动学软件进行药动学参数的分析和计算.结果:单次给药替加氟Cmax为(1407±383)ng·mL-1,AUC0-t为(15 403±8439)ng·h·mL-1,活性代谢物5-氟脲嘧啶Cmax为(128±36)ng·mL-1,AUC0-t为(539±138)ng·h·mL-1,吉美嘧啶Cmax为(222±93)ng·mL-1,AUC0-t为(962±390)ng·h·mL-1,奥替拉西Cmax为(33.2±14.6)ng·mL-1,AUC0-t为(117±64)ng·h·mL-1.与单次给药相比,多次给药后替加氟的Cmax和AUC增加明显(P<0.05),但其增加程度与理论蓄积系数接近,而代谢物氟脲嘧啶、吉美嘧啶及奥替拉西的Cmax和AUC无明显增加.受试者在研究期间未出现重度以上不良反应.结论:口服替吉奥片后,受试者耐受良好.多次给药后,替吉奥片主要成分的药代动力学行为没有发生明显变化.     

分次剂量卡铂联合X线对Lewis肺癌小鼠免疫功能的影响

背景与目的: 卡铂作为第二代铂类抗肿瘤药,已越来越多地应用于临床多种恶性肿瘤的治疗.但大剂量应用时骨髓抑制明显,结合放疗时更为显著.本文通过动物实验,探讨卡铂分次给药联合X线治疗小鼠Lewis肺癌时对其免疫功能的影响.方法: 采用在小鼠右前腋窝接种Lewis肺癌细胞的荷瘤小鼠模型,观察在总剂量相同情况下,卡铂单次与分次给药联合x线照射小鼠Lewis肺癌时对肿瘤生长及其免疫功能的影响.结果: 对照组小鼠血清IL-10、TNF-α、脾指数分别为(144.9±48.4)ng/ml、(194.63±64.4)ng/ml、(12.07±2.2)mg/g;卡铂单次给药 X线组分别为(279.0±46.9)ng/ml、(71.5±8.4)ng/ml、(5.52±1.31)mg/g,与对照组相比,IL-10水平明显升高、TNF-α水平和脾指数降低(P<0.001);卡铂分次给药 X线组分别为(209.0±60.6)ng/ml、(121.9±32.7)ng/ml、(7.67±1.23)mg/g,与对照组相比,亦是IL-10水平明显升高、TNF-α水平和脾指数降低(P<0.05),该对比结果相对于卡铂单次给药 X线组与对照组比较的结果,对小鼠IL-10的含量、TNF-α的含量和脾指数影响则明显减轻,差异有显著性(P<0.05).结论: 在总剂量相同情况下,卡铂分次给药结合X线照射,较单次给药对小鼠机体的免疫功能抑制作用要小.     

多次重复静脉应用氨甲环酸减少初次全髋关节置换术失血有效性与安全性的前瞻性对照研究

目的探讨多次重复静脉应用氨甲环酸(tranexamic acid,TXA)减少初次全髋关节置换术(total hip arthroplasty,THA)围手术期失血的有效性及安全性。方法选择2014年12月至2015年9月拟行初次THA患者90例,按TXA的不同用法以数字表法随机分为3组。单次给药组:30例术前静脉滴注TXA20 mg/kg;重复给药组:30例术前静脉滴注TXA 20 mg/kg后,3 h再次静脉滴注TXA 10 mg/kg;多次给药组:30例术前静脉滴注TXA 20 mg/kg后,3、6 h再次静脉滴注TXA 10 mg/kg。3组均于术中3个时点局部使用总量1.5 g的TXA。主要指标为隐性失血量、术后血红蛋白下降最大值、总失血量、输血率、术后血栓发生事件;次要指标为术后引流量、住院时间及伤口并发症。结果多次给药组隐性失血量(308.21±221.91)ml、总失血量(589.34±190.85)ml、血红蛋白下降最大值(20.07±6.06)g/L、均明显低于重复给药组(509.91±237.82)ml、(815.57±234.31)ml、(25.53±8.30)g/L、和单次给药组(681.86±380.82)ml、(1037.53±367.68)ml、(29.60±10.30)g/L,差异有统计学意义(P0.05)。重复给药组总失血量为(815.57±234.31)ml、引流量(180.67±77.68)ml低于单次给药组(1037.53±367.68)ml、(240.67±81.79)ml,差异有统计学统意义(P0.05)。血红蛋白下降最大值(25.53±8.30)g/L低于单次给药组(29.60±10.30)g/L,差异无统计学统意义(P0.05)。3组患者输血率均为0,无一例出现肺栓塞及下肢深静脉血栓。结论在THA术中使用TXA可以减少患者围手术期隐性失血及血红蛋白丢失,且不增加血栓风险。多次重复应用TXA可有效安全的进一步减少围手术期隐性失血及血红蛋白丢失,其中以3 h、6 h多次给药效果显著。     

富硒大蒜对犬连续口服给药12周的长期毒性试验研究

背景与目的:研究富硒大蒜连续给药后对犬的毒性反应.材料与方法:采用Beagle犬24只,随机分为给予富硒大蒜不同剂量的3个给药组(3.00 g/kg、1.50 g/kg和0.75 g/kg)和1个对照组(不服用富硒大蒜),连续口服给药12周,停药后观察2周,实验期间进行一般症状观察,检查血象、生化、心电图、尿液等,动物处死后计算脏器系数和并进行组织病理学检查.结果:给药期高剂量组的犬间断性出现呕吐,且摄食量减少,血清总胆红素明显升高,白蛋白降低,胸腺和脾脏的系数值有一定升高.除中剂量组给药期总胆红素升高外(P＜0.01),其余各剂量组各期间的各检测指标与对照组间的差异均无统计学意义,各组犬给药期和停药恢复期未见其它的毒性反应.结论:富硒大蒜在相当于临床人拟用量30倍下,仅出现轻度消化道刺激症状和血清总胆红索数值的升高.犬用药的无明显毒性反应剂量为0.75 g/kg.     

注射用紫杉醇脂质体与紫杉醇注射液在肿瘤患者中的药动学比较

目的:建立人血浆中紫杉醇(paclitaxel,PTX)浓度的液相色谱-质谱(liquid chromatography-mass spectometry,LC-MS)检测方法,比较注射用紫杉醇脂质体(paclitaxelliposomeforinjection,L-PTX)和常规紫杉醇注射液(conventional paclitaxel injection,C-PTX)在肿瘤患者中的药动学特征。方法:采用随机、开放和对照的试验设计方案。试验分2组,每组各8例患者,分别静脉滴注175mg/m2L-PTX或C-PTX,并于静脉滴注过程中的1.5和3h及滴注结束后的0.25、0.5、1、2、4、8、12、24、36、48和72h采集受试者血样。LC-MS法测定血药浓度,应用DAS2.0软件计算药动学参数并进行比较。结果:患者单次静脉滴注175mg/m2L-PTX与C-PTX的主要药动学参数:血浆峰浓度(Cmax)分别为6455±2247和7400±1542μg/L;药物血浆浓度-时间曲线下面积(area under the plasma concentration-time curve,AUC0-∞)分别为14812±2846和21693±2657μg·h·L-1;血浆消除半衰期(t1/2z)分别为30.5±7.3和13.7±3.2h;表观分布容积(Vz)分别为526.8±112.1和162.9±49.1L/m2;血浆清除率(plasmaclearance,CLz)分别为12.3±2.7和8.2±1.0L·h-1·m-2。经统计学分析,2组的药动学参数差异有统计学意义(P<0.05)。结论:脂质体包裹后改变了PTX的体内药动学特性,与常规PTX相比,脂质体制剂在肿瘤患者体内的分布特性和消除情况有显著不同,具有更好的组织亲和性与缓释作用。     

马钱子碱经皮给药对乳腺癌骨转移抑制机制的探讨

目的:探讨马钱子碱经皮给药对乳腺癌骨转移的抑制机制,为乳腺癌的治疗提供新的途径.方法:培养人乳腺癌细胞株MDA-MB-231,取对数生长期细胞制成单细胞悬液.20只雌性Balb/c-nu/nu裸鼠麻醉后,无菌条件下,局部骨内注射乳腺癌单细胞悬液0.2 mL,复制乳腺癌骨转移模型.20只荷瘤裸鼠随机分为马钱子碱高剂量组、中剂量组、低剂量组和模型组4组,分别给予20％(0.2 mg/g)、10％(0.1 mg/g)和5％(0.05 mg/g)浓度的马钱子碱膏(每日总剂量≤腹腔给药的半数致死量)和凡士林经皮给药,涂抹裸鼠的整个腹部和造模的部位,1 g/次,4次/d(每次间隔3 h),连续15 d.影像学观察骨转移情况;RT-PCR检测并比较各组肿瘤组织中,骨转移相关因子VEGF、COX-2和PTHrP的表达量.结果:胫骨的X射线表现,马钱子碱高剂量组和中剂量组的骨质破坏不明显,低剂量组和模型组的骨质破坏明显,甚至出现病理性骨折.RT-PCR结果显示,钱子碱高剂量组VEGF、COX-2和PTHrP mRNA的表达分别为25.30±0.90、20.63±0.73和25.56±0.54,马钱子碱中剂量组分别为24.10±0.73、20.49±0.76和25.74±0.48,马钱子碱低剂量组分别为25.27±0.75、21.02±0.65和25.65±0.44,模型组分别为24.09±0.74、21.14±0.66和25.75±0.39.与模型组比较,马钱子碱各剂量组VEGF、COX-2和PTHrP mRNA的表达量随着马钱子碱剂量的增加逐渐下降,差异均有统计学意义,P＜0.05.结论:马钱子碱经皮给药能抑制裸鼠乳腺癌骨转移瘤的生长,减轻骨损伤,其机制可能是通过调控VEGF、COX-2和PTHrP的表达而抑制乳腺癌骨转移瘤的生长.     

注射用纳米羟基喜树碱的药代动力学和组织分布研究

目的:观察注射用纳米羟基喜树碱(HCPT纳米针)静脉推注后在家免血浆药物浓度随时间变化趋势和药动学参数以及小鼠体组织分布特征.方法:建立HPLC检测家兔血浆和小鼠各组织中羟基喜树碱含量的方法;绘制3个剂量组(2.5、5.0、7.5mg/kg)家免血浆药-时曲线并采用3p97软件模拟房室模型并计算药动学参数;BALB/c小鼠给予HCPT纳米针(10mg/kg)后,检测15min、1h和2h各组织和血浆中羟基喜树碱的含量.结果:1)HCPT纳米针家免耳静脉单次给药符合1/C2权重的三室模型,AUC和Vd等药动学参数在既定药物浓度范围内呈线性改变.2)HCPT纳米针在肝组织中浓度最高,分布顺序:肝＞肾＞脾＞肠＞胃＞肺＞心.3)HCPT纳米针给药后在肝组织保留时间长.结论:HCPT纳米针在肝组织中药物浓度高、存留时间长,具有明确的靶向性.     

静脉注射福大赛因对昆明小鼠的皮肤光毒性

背景与目的:研究福大赛因对小鼠的皮肤光毒性.材料与方法:将昆明小鼠随机分为5组,分别为生理盐水组(给予生理盐水0.02 ml/g),溶剂对照组[给予溶剂0.02 ml/g).福大赛因低剂量组(2 mg/kg)和高剂量组(5 mg/kg)以及阳性对照组(给予血卟啉15 mg/kg).均采用静脉注射1次性给药.小鼠于给药后的不同时间接受不同强度模拟太阳光照射60 min.用6 mm打孔器取左、右耳廓各1耳片,并称重,通过小鼠耳片重量和肿胀率的变化评价皮肤光毒性.结果:福大赛因高、低剂量组于给药后1、3及24h接受模拟太阳光(40 mW/cm2)照射后,耳片重量与对照组相比显著增加(P<0.05),而低剂量组于给药后48 h照射后无明显异常,高剂量组则给药后7 d经照射无明显异常.给药后1、3 h不同强度模拟太阳光照射(10、20、30、40 mW/cm2),各组小鼠均出现毒性反应;10 mW/cm2组耳片重量与20、30、40 mW/cm2组间差异具有统计学意义(P<0.01).结论:福大赛因2 mg/kg体重给药48 h后光照无明显光毒性反应;5 mg/kg给药7 d后光照无明显光毒性反应.福大赛因产生光毒性的饱和光强度约为20 mW/cm2     

Pharmacology and toxicity of nicotinamide combined with domperidone during fractionated radiotherapy.

BACKGROUND AND PURPOSE: Treatment of head and neck tumors by the ARCON regimen has yielded high local control rates. As a result of this treatment intensification there was some increase in mainly acute toxicity of radiotherapy, but nicotinamide by itself has specific side effects such as nausea and vomiting. Due to these side effects and with the initial dose of 80 mg/kg, 31% of the patients discontinued nicotinamide intake. The aim of the study was to investigate the effect of a dose reduction to 60 mg/kg, and the addition of domperidone on the side effects of nicotinamide and its pharmacokinetic profile. PATIENTS AND METHODS: In 22 patients blood plasma nicotinamide levels were determined after intake of 60 mg/kg nicotinamide. A next group of 87 patients received 60 mg/kg nicotinamide in combination with domperidone. In ten of these patients blood plasma nicotinamide levels were also determined. A full pharmacokinetic profile was constructed over the first 24 h after intake of the first drug dose. Furthermore, daily plasma levels at 1 h after nicotinamide intake was determined in the first and last weeks of radiotherapy. All patients were treated according to the ARCON schedule. RESULTS AND DISCUSSION: The mean maximum plasma nicotinamide concentration was 793 nmol/ml without domperidone and 776 nmol/ml with domperidone. The median time at which the maximum concentration occurred was not significantly different for 60 mg/kg nicotinamide without or with domperidone (0.46 versus 0.54 h). The side effects were drastically reduced if nicotinamide was accompanied by domperidone. The percentage of patients that stopped nicotinamide intake was reduced from 32% without domperidone to 14% with domperidone. No correlation was found between the plasma peak concentrations of nicotinamide and the severity of side effects. CONCLUSION: The currently used dose of 60 mg/kg nicotinamide results in a 30% reduction in peak plasma concentrations compared with 80 mg/kg nicotinamide. If nicotinamide was given in combination with domperidone, 86% of the patients continued the nicotinamide medication until the end of the treatment period.     

钬元素对小鼠肝脏细胞DNA损伤的影响

背景与目的: 通过研究钬离子溶液对小鼠肝脏细胞DNA的损伤,探讨钬元素对诱导动物细胞凋亡的影响 。材料与方法: 处理组1： 小鼠定时灌胃氯化钬溶液50 mg/(kg•d),连续5 d; 组 2～3： 小鼠分别定时腹腔注射氯化钬溶液60 mg/(kg•d)和120 mg/(kg•d),连续2 d; 组4： 小鼠一次性腹腔注射氯化钬溶液320 mg/kg; 每次染毒相间24 h,组1～4： 小鼠均在末次染毒24 h后处死,提取肝脏DNA。 组5： 小鼠一次性腹腔注射等体积生理盐水; 组6～9： 小鼠一次性腹腔注射氯化钬溶液80 mg/kg,分别于注射后12、24、48和96 h处死小鼠提取肝脏DNA。通过琼脂糖凝胶电泳研究各组DNA带型变化。 结果：处理组7 DNA电泳中出现连续的弥散带型,其它各组均未观察到明显的拖尾现象。也未观察到“DNA ladder"。 结论： 钬离子对小鼠肝脏细胞DNA的断裂作用可能与其剂量大小、处理时间及DNA修复作用有关,而且无特异性。本实验结果表明,钬元素未诱导小鼠肝脏细胞凋亡。     

A Phase I clinical and pharmacological evaluation of sodium phenylbutyrate on an 120-h infusion schedule.

PURPOSE: Sodium phenylbutyrate (PB) demonstrates potent differentiating capacity in multiple hematopoietic and solid tumor cell lines. We conducted a Phase I and pharmacokinetic study of PB by continuous infusion to characterize the maximum tolerated dose, toxicities, pharmacokinetics, and antitumor effects in patients with refractory solid tumors. PATIENTS AND METHODS: Patients were treated with a 120-h PB infusion every 21 days. The dose was escalated from 150 to 515 mg/kg/day. Pharmacokinetics were performed during and after the first infusion period using a validated high-performance liquid chromatographic assay and single compartmental pharmacokinetic model for PB and its principal metabolite, phenylacetate. RESULTS: A total of 24 patients were enrolled on study, with hormone refractory prostate cancer being the predominant tumor type. All patients were evaluable for toxicity and response. A total of 89 cycles were administered. The dose-limiting toxicity (DLT) was neuro-cortical, exemplified by excessive somnolence and confusion and accompanied by clinically significant hypokalemia, hyponatremia, and hyperuricemia. One patient at 515 mg/kg/day and another at 345 mg/kg/day experienced this DLT. Toxicity resolved < or =12 h of discontinuing the infusion. Other toxicities were mild, including fatigue and nausea. The maximum tolerated dose was 410 mg/kg/day for 5 days. Pharmacokinetics demonstrated that plasma clearance of PB increased in a continuous fashion beginning 24 h into the infusion. In individuals whose V(max) for drug elimination was less than their drug-dosing rate, the active metabolite phenylacetate accumulated progressively. Plasma PB concentrations (at 410 mg/kg/day) remained above the targeted therapeutic threshold of 500 micromol/liter required for in vitro activity. CONCLUSION: The DLT in this Phase I study for infusional PB given for 5 days every 21 days is neuro-cortical in nature. The recommended Phase II dose is 410 mg/kg/day for 120 h.     

2-(α-羟基戊基)苯甲酸钾盐的急性毒性和致突变作用研究

目的:研究2-(α-羟基戊基)苯甲酸钾盐(dl-PHPB)的急性毒性及致突变性。方法:急性毒性试验采用Bliss法,昆明小鼠分为5组,每组10只,雌雄各半,分别按256.0、286.3、320.0、357.8、400.0、447.2 mg/kg静脉注射dl-PHPB,观察注射后至给药后14 d动物的毒性反应性质及程度,计算半数致死剂量(LD₅₀)及95%可信限;Ames试验采用平板掺入预培养法,选用鼠伤寒沙门氏菌株TA97、TA98、TA100和TA102,每皿0.5～5 000.0 μg浓度范围内,检测加和不加S9条件下对Ames菌的致突变性;微核试验采用雄性昆明小鼠,分为3组,每组6只,分别按23.3、70、210 mg/kg单次静脉注射dl-PHPB,注射后24 h计数骨髓嗜多染红细胞微核率(MNPCEs);体外染色体畸变试验在加和不加S9条件下,检测11.0~88.0 μg/mL dl-PHPB对CHL细胞染色体畸变率的影响。结果:小鼠静脉注射dl-PHPB后,各剂量动物出现一过性呼吸急促、自发活动减少、俯卧少动等症状,随剂量增加至≥320.0 mg/kg时,部分动物出现濒死症状,并在给药后2~30 min内死亡,死亡率随剂量的增加而增加,256.0~447.2 mg/kg 6个剂量组死亡率依次为0、0、10%、30%、70%、100%。未死亡动物在给药30 min后逐渐恢复正常。14 d观察期期间动物未见其他异常。其LD₅₀为373.3 mg/kg,95%可信限为355.6～392.0 mg/kg;Ames试验结果显示,在每皿0.5～5 000.0 μg浓度范围内未引起4种测试菌株回复突变数增加;微核试验结果显示,dl-PHPB在23.3~210.0 mg/kg范围内,各组动物MNPCEs均低于4‰;CHL细胞体外染色体畸变试验中,dl-PHPB在 11.0～88.0 μg/mL浓度范围内致CHL细胞染色体畸变率<5%。结论:在本实验条件下,小鼠静脉注射dl-PHPB的LD₅₀为373.3 mg/kg,致突变性3项试验均为阴性结果。     

In vivo evaluation of a novel antitumor prodrug, 1-(2'-oxopropyl)-5-fluorouracil (OFU001), which releases 5-fluorouracil upon hypoxic irradiation

PURPOSE: We previously proposed that a prodrug of 5-fluorouracil (5-FU), OFU001, is activated through capturing of hydrated electrons produced by hypoxic irradiation. Because hydrated electrons are readily deactivated by oxygen, the 5-FU release occurs specifically upon hypoxic irradiation. In this study, we investigated the in vivo efficacy, pharmacokinetics, and toxicity of OFU001. METHODS AND MATERIALS: Female 10-week-old C3H/He mice bearing SCCVII tumors were used. To measure release of 5-FU from OFU001 in vivo, the mice were given 100 mg/kg of OFU001 intraperitoneally and irradiated. Thereafter, 5-FU levels in the tumor and serum were measured by high-performance liquid chromatography. To evaluate in vivo efficacy, OFU001 was administered 30 min before irradiation, and radiation-potentiating effects were investigated by means of a tumor growth delay assay and a 50% tumor control dose (TCD-50) assay. The lethal dose of OFU001 was evaluated in the same mice. RESULTS: Following administration of OFU001 and irradiation at 30 Gy, the average 5-FU levels in the tumor and serum were 179 ng/g and 83 ng/mL, respectively. Administration of OFU001 (100-200 mg/kg) to the tumor-bearing mice before a single dose of 15-Gy irradiation produced a mean tumor growth delay of 1-5 days as compared to radiation alone (although the delay was not significant). However, no additional growth delay was observed when OFU001 was combined with 5 radiation fractions of 4 Gy each. The enhancement ratio of OFU001 in the TCD-50 assay was 1.2. No mice died after administration of 0.6-1.2 g/kg of OFU001. CONCLUSIONS: OFU001 appears to work in vivo via the proposed mechanism of activation. Although the in vivo effect of this compound was not strong enough for clinical efficacy, these results should encourage further research on the development of prodrugs of more potent anticancer agents activated through the same mechanism.     

Therapeutic effects of Lycium barbarum polysaccharide (LBP) on irradiation or chemotherapy-induced myelosuppressive mice

AIM: The aim of this study was to investigate the effects of Lycium barbarum polysaccharide (LBP) on irradiation- or chemotherapy-induced myelosuppressive mice and cultured peripheral blood mononuclear cells (PBMCs). METHODS: In an in vivo experiment, mice were irradiated with a sublethal dose of 550 cGy X-ray or intraperitoneally (i.p.) injected with carboplatin (CB) 125 mg/kg to produce severe myelosuppression. Four to 6 hours after the irradiation or injection, mice were subcutaneously (s.c.) injected with LBP (50, 100, and 200 mg/kg) daily from day 0 to day 6. Blood samples were collected from the tail veins of mice at different time points, and peripheral white blood cells (WBC), red blood cells (RBC), and platelet (PLT) counts were monitored. In an in vitro experiment, human PBMCs were incubated with LBP at different concentrations in combination with phytohemagglutinin (PHA), and the production of granulocyte colony-stimulating factor (G-CSF) was tested. RESULTS: Compared to the control, 50 mg/kg LBP (LBP-L) significantly ameliorated the decrease of peripheral WBC of irradiated myelosuppressive mice on day 13, and 100 mg/kg LBP (LBP-M) did the same on days 17 and 21. All dosages of LBP significantly ameliorated the decrease of peripheral RBC of irradiated myelosuppressive mice on days 17 and 25. Two-hundred mg/kg LBP (LBP-H) and LBP-M significantly enhanced peripheral PLT counts of irradiated myelosuppressive mice on days 10, 13, 17, and 21, as did LBP-L on days 13 and 17. All dosages of LBP increased peripheral WBC counts of chemotherapy-induced myelosuppressive mice to some extent, but there was no statistic difference when compared to the control. LBP-H significantly ameliorated the decrease of peripheral RBC of chemotherapy-induced myelosuppressive mice on days 13, 15, 17, and 20, and LBP-M and LBP-L did the same on days 15 and 17. All dosages of LBP significantly enhanced peripheral PLT counts of chemotherapy-induced myelosuppressive mice on days 7 and 10, as did LBP-H on days 13, 15, and 17, and LBP-M on days 13 and 15. Also, LBP could obviously stimulate human PBMCs to produce G-CSF. CONCLUSIONS: LBP promoted the peripheral blood recovery of irradiation or chemotherapy-induced myelosuppressive mice, and the effects may be the result of the stimulation of PBMCs to produce G-CSF.     

Potential and toxicity of intravesical pemetrexed: a preclinical study in pigs.

PURPOSE: In search for a new drug for intravesical use in superficial urothelial cell carcinoma of the bladder, a pig model is used for pharmacokinetics and toxicity measurements after intravesically administered pemetrexed. EXPERIMENTAL DESIGN: In the dose escalation phase, two groups of two pigs received 5 and 10 mg/kg pemetrexed intravesically; four groups of three pigs received 15, 20, 25, and 30 mg/kg, respectively. The well-being of the animals was monitored. Blood was studied for pharmacokinetic analysis and signs of myelosuppression. Posttreatment urine samples were collected to measure the concentration of pemetrexed after instillation. Twenty-four hours posttreatment, the animals were cystectomized and sacrificed. Histopathologic examination of the bladder wall was done. In the second study phase, five pigs were instilled weekly with the maximum tested dose for 6 weeks. The same methods were applied. RESULTS: All doses (5-30 mg/kg) in the first study phase were well tolerated, enabling the use of 30 mg/kg in the second study phase. In both study phases, the pigs' well-being was not influenced. Full blood counts showed no sign of myelosuppression. Systemic absorption was not observed. Urine pemetrexed concentrations remained almost unchanged. Histopathologic examination of the bladder wall did not reveal significant abnormalities. Bladder mucosa remained intact at any time, without hemorrhage. CONCLUSIONS: Intravesically administered pemetrexed in pigs is well tolerated, not absorbed systemically, and causes no bladder wall toxicity.     

Human pharmacokinetics, excretion, and metabolism of the anthracycline antibiotic menogaril (7-OMEN, NSC 269148) and their correlation with clinical toxicities

In a Phase I study, menogaril (7-OMEN) was administered daily for 5 days/course, every 21-28 days. Dosages of 3.5, 7, 11.5, 17, and 31.5 mg/m2 were infused over 1 h, and dosages of 42, 50, and 56 mg/m2 were infused over 2 h. Pharmacokinetics was studied at all dosages. Plasma and urine samples were collected from 24 patients, and bile samples were also collected from 2 patients. 7-OMEN and metabolites were measured by high performance liquid chromatography. 7-OMEN was the major plasma fluorescent species at all times, with only trace amounts of N-demethyl menogaril observed. 7-OMEN disappeared from plasma biexponentially with t1/2 alpha 0.19 +/- 0.04 (mean +/- SE) h and t1/2 beta 13.22 +/- 1.54 h. Plasma pharmacokinetics of 7-OMEN was linear from 3.5-56 mg/m2; area under the curve increased proportionally with dosage. Total body clearance of 7-OMEN was 28.18 +/- 3.33 liter/m2/h, Vc was 224 +/- 30.8 liter/m2, and Vss was 370 +/- 25.7 liter/m2. Plasma pharmacokinetics of 7-OMEN studied on multiple days of a given course were similar. Urinary excretion of 7-OMEN and fluorescent metabolites accounted for 5.4 +/- 0.4% of the daily dose. Parent compound still represented greater than or equal to 80% of urinary drug fluorescence after 24 h. N-demethyl menogaril was the only other fluorescent drug species detected in urine. In two patients with biliary tract drains, biliary excretion of drug fluorescence accounted for 2.2-4.2% of the daily dose. Only 7-OMEN and N-demethyl menogaril were detected in bile by high performance liquid chromatography and thin layer chromatography. 7-OMEN was the major fluorescent biliary species, but, by 24 h, N-demethyl menogaril accounted for approximately 40% of biliary drug fluorescence. When considered in light of each patient's observed toxicities, excellent relationships were observed between the plasma area under the curve of 7-OMEN and the percentage of decreases in WBC and absolute neutrophil count. These latter findings should be useful in developing more precise and intelligent dosing schemes for 7-OMEN.     

1-氯甲基杂氮硅三环对大鼠致畸毒性试验

背景与目的： 观察1-氯甲基杂氮硅三环对大鼠的致畸毒性。 材料与方法： 将SD孕鼠随机分为1-氯甲基杂氮硅三环高、中、低3个不同剂量(10.29、32.54、102.89 mg/kg)的给药组,以及溶剂对照组(3％淀粉糊)和敌枯双阳性对照组(1 mg/kg),共5组。大鼠妊娠第6～15 d每天灌胃染毒1次,妊娠第20 d处死,检查各项指标。 结果： 1-氯甲基杂氮硅三环中、高剂量组胎仔骨骼畸形率较溶剂对照组增加(P<0.05或P<0.01),主要表现为胸骨骨化不全、缺失和形状异常等,其最小致畸量为32.54 mg/kg;各剂量组孕鼠的体重和胚胎毒性与阴性对照组比较差异无统计学意义(P>0.05);各剂量组胎仔的生长指标、外观和内脏均未见异常。 结论： 在本实验条件下, 1-氯甲基杂氮硅三环一定剂量下对SD大鼠有致畸毒性。